Case studyMutation of the INI1 gene in composite rhabdoid tumor of the endometrium☆
Introduction
The INI1/SNF5/SMARCB1 gene at chromosomal band 22q11.2 encodes a member of the SWI/SNF chromatin remodeling complex. This complex is a negative regulator of the cell cycle, modulates cytoskeleton organization, and functions as a tumor suppressor gene [1], [2], [3], [4], [5], [6]. Homozygous deletion of both alleles of the INI1 gene or deletion of one allele and mutation of the second allele results in the development of rhabdoid tumors of the kidney, central nervous system, soft tissue, or liver in infants and young children [2], [6], [7], [8], [9]. Most mutations are single-base-pair, nonsense mutations, and frameshifts that introduce a novel stop codon, and predict a prematurely truncated protein [9]. In practice however, the INI1 protein is not detectable, and a virtually diagnostic feature of these pediatric rhabdoid tumors is their lack of immunoreactivity with monoclonal antibodies against the INI1 protein [10], [11], [12].
Tumors that are morphologically similar to pediatric rhabdoid tumors can also develop in adult patients, often in tumors of diverse histogenesis (carcinomas, sarcomas, melanomas, gliomas, meningiomas) [13], [14], [15], [16], [17], [18], [19], [20], [21]. These tumors, in contrast to pediatric rhabdoid tumors, typically retain the INI1 gene, and are immunoreactive with antibodies to BAF47 [22]. The molecular pathogenesis of these tumors is not known. Neither deletion nor mutation of the INI1 gene was present in a disseminated uterine rhabdoid tumor that was likely of endometrial origin [15]. In a recent study of 40 composite rhabdoid tumors, most of them arising in adult patients, loss of immunoreactivity for the INI1 protein was found only in a single tumor, a rhabdoid component of a leiomyosarcoma [22]. For technical reasons, it was not possible to determine whether the INI1 gene was mutated, but no deletion of 22q was detected in the tumor by fluorescence in situ hybridization with a probe to the BCR gene, which is proximal to INI1 within 22q11.2 [21], [22].
We present a case of endometrial composite rhabdoid tumor with deletion of one copy of the INI1 gene, mutation of the second allele, and lack of immunoreactivity with the BAF47 antibody, the features typical for rhabdoid tumors. In contrast, the second endometrial tumor was immunopositive with antibody BAF47 and, thus, has presumptively a distinct molecular etiology.
Section snippets
Case 1
A 51-year-old woman presented with a hemorrhagic and partially necrotic fleshy tan endometrial mass measuring 12.0 × 7.5 × 2.5 cm, with pushing border, invading 80% of the myometrial thickness. Hysterectomy and bilateral salpingo-oophorectomy were followed by radiation therapy. She is alive and free of disease 14 months after surgery.
Case 2
A 71-year-old woman presented with a hemorrhagic pale tan endometrial mass measuring 7.0 × 5.0 × 1.5 cm, which invaded 50% of myometrial thickness and extended to
Discussion
Our results show a similar mechanism of tumorigenesis between a minority of composite rhabdoid tumors of adulthood and classic pediatric rhabdoid tumors. Loss of one INI1 allele and mutation of the remaining allele were followed by the development of the rhabdoid tumor component. The mechanisms of tumorigenesis in most composite rhabdoid tumors remain poorly elucidated. The rhabdoid components in these tumors are, in contrast to pediatric rhabdoid tumors, typically immunoreactive with the BAF47
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The significance of SMARCB1 in the pathogenesis of renal cell carcinoma with rhabdoid features
2021, Translational OncologySWI/SNF-deficient malignancies of the female genital tract
2021, Seminars in Diagnostic PathologyCitation Excerpt :It is possible that the two SMARCA4-deficient high-grade endometrial stromal sarcomas in this study represent the SMARCA4-deficient undifferentiated uterine sarcomas initially described by Kolin and colleagues.52,53 There are also occasional reports of SMARCB1 (INI1)-deficient uterine carcinosarcoma and proximal-type epithelioid sarcoma, but it is unclear whether such cases might now be reclassified as UEC/DEC.55,56 This also applies to some previously reported uterine neoplasms exhibiting rhabdoid morphology, sometimes classified as “rhabdoid tumour”, that were not subject to SWI/SNF complex analysis.57,58 Undifferentiated and dedifferentiated (associated with a component of low-grade endometrioid carcinoma) carcinomas, exactly analogous to those discussed earlier in the endometrium, also occur within the ovary.12
Benign Lesions of Soft Tissue With Epithelioid/Epithelial-Like Appearances
2019, Practical Soft Tissue Pathology: A Diagnostic Approach A Volume in the Pattern Recognition SeriesPattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: Analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant
2015, Annals of Diagnostic PathologyCitation Excerpt :It is likely that different secondary mechanisms might be responsible for this phenotypic shift. Three previous case reports illustrated that SMARCB1 loss is associated with a transition from low-grade endometrioid carcinoma to an undifferentiated (rhabdoid) component that was reported as uterine rhabdoid tumor [20,21] and proximal-type epithelioid sarcoma of the uterus [22]. Presence of a low-grade endometrioid component justified the term collision tumor [20] or composite rhabdoid tumor [21].
Immunohistochemical validation of INI1/SMARCB1 in a spectrum of musculoskeletal tumors: An experience at a tertiary cancer referral centre
2013, Pathology Research and PracticeCitation Excerpt :All 7 cases of carcinoma with a variable number of ‘rhabdoid-like’ cells showed intact INI1 expression. Rarely, loss of INI has been documented in composite tumor of the endometrium, comprising adenocarcinoma and sarcoma, including rhabdoid cells and another case of a pancreatic mucinous adenocarcinoma with rhabdoid cells [37,38]. Both cases of epithelioid hemangioendothelioma and epithelioid angiosarcoma displayed positive INI1 immunostaining.
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This study was supported by grants CA46274 and CA98543 from the National Institutes of Health (to J.A.B.).